The ultimate goals of the project are to improve drug therapy and decrease the toxicity of drugs, economic poisons and carcinogens through a better understanding of the functions of the hepatic cytochrome P-450-linked mixed function oxidase (MFO) systems that both detoxify and activate these xenobiotics. Studies of microsomal P-450 systems present special problems because they are membrane-bound and they exist in multiple forms; they are unique because they both transfer electrons and hydroxylate substrates. The application is comprised of seven major projects which will attempt to answer some of the many questions regarding these systems: a) determination of the electron spin characteristics of P-450 by analysis of optical spectra; b) measurements of the rates of resynthesis of individual MFO activities after their selective destruction by agents such as allylisopropylacetamide (AIA) which destroy the heme of P-450; c) studies which will attempt to answer the question of whether hepatic P-450 can transport molecular oxygen; d) studies of the mechanism of the reduction of ferricytochrome P-450 reductase; e) studies designed to determine the oxygen affinities of different molecular species of hepatic P-450; f) studies of the mechanism of substrate-induced hydrogen peroxide production by hepatic P-450's; g) studies of the possibility that intermediate metabolites of inducing agents may initiate the induction of MFO systems.